1. Description of the problem

Fluid therapy is an integral aspect of the acute resuscitation of critically ill patients. Moreover, fluid therapy is likely one of the only effective strategies for prevention of acute kidney injury. Practically all patients receive intravenous fluid therapy, in variable quantities and forms, during an episode of critical illness. Importantly, there is general consensus that fluid therapy should be given early and targeted to physiologic endpoints such as mean arterial pressure, cardiac output, central venous pressure and urine output, in particular for clinical syndromes such as severe sepsis/septic shock.

The notion of early goal-directed therapy (EGDT), shown to reduce mortality in a single-center trial of 263 septic shock patients presenting to an urban emergency department, as a general principle for acute resuscitation has been considered ground-breaking and is now well integrated into clinical practice and practice guidelines. In the EGDT trial by Rivers and colleagues, at 72 hours, all enrolled septic patients had received approximately 13-14 L of resuscitation fluid, composed of crystalloid, colloid and transfused blood products.

Unfortunately, no specific details were provided on cumulative fluid balance, oliguria or rates of acute kidney injury (AKI). However, these data clearly show that fluid accumulation, and with it the risk for fluid overload, in critically ill patients is common and may be to a large extent inevitable in the early phases of illness. These observations are further supported by data from several Acute Respiratory Distress Syndrome (ARDS) Network trials that show critically ill patients with acute lung injury (ALI) accumulate an average of 1 L per day (approximately 4-7 L over the first week) following their acute resuscitation.

Aggressive resuscitation, of which fluid therapy is a critical component, is a clear priority in the acute phase of shock states, in particular in sepsis, to rapidly restore tissue perfusion and correct cellular hypoxia. However, following this acute phase of resuscitation, a threshold may exist where the perceived benefit of additional fluid therapy may not outweigh the potential risk of morbidity associated with significant fluid accumulation.

For example, in a small cohort study of critically ill septic patients with AKI, Van Biesen and colleagues showed that continued administration of fluid therapy, despite apparent optimized systemic hemodynamics, replete intravascular volume, and a high rate of diuretic use, leads to worsening gas exchange and pulmonary edema due to unnecessary fluid accumulation, with no meaningful improvement in kidney function.

Indeed, a positive fluid balance has been associated with worse clinical outcomes across a range of clinical settings, including elective colorectal surgery, ALI, septic shock, AKI, and in critical illness in general, as well as in both pediatric and adult populations. In addition, the development of oliguria and/or AKI is common in critical illness, and may further impair free water and solute excretion. This will almost universally translate and compound fluid accumulation. Moreover, clinical studies have shown maintaining a neutral or negative fluid balance may improve clinical outcomes in critically ill patients with ALI and pulmonary edema and be predictive of successful weaning from mechanical ventilation.

Accordingly, fluid balance should be routinely monitored and considered an important biomarker for critically ill patients.

Key management points

For all patients with volume overload, limit and/or restrict all non-essential fluid therapy

For all patients with volume overload, following the acute resuscitative phase of critical illness, initiate fluid mobilization as tolerated with diuretic therapy as necessary

For all patients with volume overload, but in particular for patients with intravascular volume overload and acute kidney injury or those with refractory extravascular volume overload, initiate extracorporeal fluid removal with renal replacement therapy.

2. Emergency Management

Stabilizing the patient

Volume overload can be a life-threatening condition, in particular when associated with interstitial and pulmonary edema that interferes with gas exchange and systemic oxygenation. This is a medical emergency. The clinical priorities when faced with these circumstances are focused on improving gas exchange to enable the systemic delivery of oxygen and mitigating cellular hypoxia, continued resuscitation to optimize systemic hemodynamics, and targeted therapy to reverse the contributing factors coupled with the rapid removal of excess extravascular lung water. The following steps should be considered in all patients:

Optimizing systemic hemodynamics and oxygen delivery – This is also critical to ensure adequate tissue delivery of oxygenated blood, and may include the addition of inotropic, vasopressor and/or vasodilator therapy for patients with impaired myocardial function, hypertensive crises or distributive shock depending on the clinical context.

Minimization of contributing factors for excess extravascular pulmonary edema – This should focus primarily on the discontinuation and/or restriction of all non-essential fluid therapy.

Removal for excess extravascular lung water – This should include a trial of diuretic therapy to induce a diuresis/natriuresis. In patients with severe hypoproteinemia (i.e., albumin < 20 g/L), diuresis may be improved by co-administration with hyper-oncotic albumin solution (i.e., albumin 25% 100 mL) by increasing serum oncotic pressure and drawing fluid into the vascular space and improved delivery of diuretic to kidney site of action. In selected patients, considerable fluid may have accumulated in the pleural space, necessitating chest tube drainage to improve ventilation and gas exchange. For patients with AKI, there may be a poor response to diuretic therapy. This should prompt insertion of a dialysis catheter and initiation of renal support for ultrafiltration.

For all patients with volume overload, limit and/or restrict all non-essential fluid therapy

For all patients with volume overload, following the acute resuscitative phase of critical illness, initiate fluid mobilization as tolerated with diuretic therapy as necessary

For all patients with volume overload, but in particular for patients with intravascular volume overload and acute kidney injury or those with refractory extravascular volume overload, initiate extracorporeal fluid removal with renal replacement therapy

Drugs and dosages

For patients with life-threatening pulmonary edema, the following drug therapy may be utilized, depending on the clinical context:

Diuretic therapy:

Furosemide 20-40 mg IV bolus OR

Bumetanide 1 mg IV bolus OR

Torsemide 10-20 mg IV bolus AND/OR

Metalozone 2.5-10 mg oral

Vasodilator therapy:

Nitroglycerin 10-200 mcg/min IV infusion

Nitroprusside 0.3-0.5 mcg/kg/min

Inotropic therapy:

Dobutamine 2.5-15 mcg/kg/min

Milrinone 0.125-0.5 mcg/kg/min

Vasopressor therapy:

Norepinephrine 0.01-0.4 mcg/kg/min

Vasopressin 0.01-0.04 U/min

Epinephrine 0.01-0.4 mcg/kg/min

3. Diagnosis

Diagnostic approach

In general, the diagnosis of volume overload can be made by a combination of a review of a patient’s medical record, a focused clinical examination, a review of laboratory parameters and selected biomarkers (i.e., brain natriuretic peptide), selected diagnostic imaging (i.e., chest x-ray), along with more novel techniques of functional hemodynamic monitoring (i.e., echocardiography) and measures of volume responsiveness (i.e., pulse pressure variation, stroke volume variation, impedance phlebography, and passive leg raising).

There is a formula that was developed for use in critically ill children and has been adapted for use in adult critically ill patients that can be used to estimate, for a given patient, the percentage fluid overload:

Where “total fluid in” is the sum total of all fluid administered to the patient in a given period of observation (i.e., since ICU admission), “total fluid out” is the sum total of all measurable fluid losses by a patient in a given period of observation (i.e., include urine, gastrointestinal, pleural, peritoneal, etc.), and “admission body weight” is the measured or estimated actual weight for a given patient at the beginning of the period of observation. An estimated measure of %FO > 10% has conventionally been used to discriminate the presence of fluid overload in both pediatric and adult studies.

Review of patient medical record

Such a review should focus on details of amount and type of fluid administered (i.e., oral, subcutaneous or intravenous). This would also include any administered enteral and parenteral nutrition. Details of measured fluid losses, such as urine, nasogastric tube losses, pleural drain output, ascites drainage, should be accounted for. There should not be an attempt to estimate “insensible” or “third space” losses, as there is no reliable method to measure such losses. However, there are selected cohorts of critically ill patients who may be at particular risk for significant insensible or third space losses that warrant consideration, including patients with burn injuries, those with acute pancreatitis, and those with a surgical open abdomen.

The medical record should also be reviewed for measures of fluid balance and accumulation over a given period of interest (i.e., peri-operative). A review of the medical record should also provide a sense of the pre-morbid status and clinical course for the patient -- for example, whether the patient had significant pre-existing illness that would predispose to fluid accumulation (i.e., heart failure, chronic kidney disease, liver disease) and whether there have been recent important changes to cardiac, lung and/or kidney function, or other clinical events (i.e., surgery, sepsis), that have contributed to pathophysiologic fluid accumulation.

Perform a focused clinical examination

Such an examination should focus on the assessment of intra-vascular and extra-vascular volume status. Such assessment is complex and imperfect. It should consider the integrated evaluation of body weight, vital signs, focused physical examination, along with information obtained through invasive and non-invasive hemodynamic monitoring. Patient weight should be measured, if possible, and compared to a baseline or “dry weight” measure.

The assessment of intra-vascular volume status should include examination of pulse rate, blood pressure, jugular venous pressure and wave forms, and precordium along with auscultation of heart sounds.

An assessment of extra-vascular volume status should include an examination for edema, mostly commonly in the peripheral and/or dependent subcutaneous tissues. However, edema can accumulate in any tissue space. In critical illness, shock and systemic inflammation contribute to a reduced effective circulation, a reduced plasma oncotic pressure gradient (i.e., hypoalbuminemia) and alterations to capillary permeability, leading to considerable fluid leakage from the vascular compartment. In response, critically ill patients often receive a high obligatory intake of hypo-oncotic fluids (i.e., active resuscitation, intravenous medications) that readily exit the vascular compartment.

Importantly, extra-vascular edema is not simply cosmetic; it can be pathophysiologic and can readily accumulate at a variety of other anatomic sites. The chest should be examined for evidence of extra-vascular lung water, including accumulating pleural effusions that may impose restrictive effects on ventilation and/or impair gas exchange. The abdomen should also be examined, including the measurement of intra-abdominal pressure and for clinical evidence of ascites. An elevated intra-abdominal pressure can impair ventilatory status and kidney venous drainage, contributing to worsening kidney function and exacerbating pathophysiologic fluid accumulation.

It is also critical to recognize that intra- and extra-vascular volumes are not necessarily concordant. For example, a patient may have intra-vascular volume overload; however, a few clinical manifestations of extra-vascular edema. Similarly, and likely a more common scenario, a patient may have abundant evidence of extra-vascular volume overload associated with his or her critical illness; however, the patient may also be intra-vascular volume deplete and insufficiently resuscitated. The clinical assessment and reliable determination of whether fluid therapy is indicated in such patients can be challenging. Given these challenges, continuous hemodynamic monitoring is a central aspect of diagnosis and titration of therapy for these patients.

Diagnostic tests

The following diagnostic tests, if available, and in addition to a medical record review and clinical examination, may support or refute the diagnosis of fluid overload in a critically ill patient:

Normal lab values

Critically ill patients with fluid overload may have some constellation of the following laboratory parameters; however, fluid overload can occur in their absence and may be context- and diagnosis-specific:

Pathophysiology

Several mechanisms contribute to the accumulation of a positive fluid balance and volume overload in critical illness. In general, a critically ill state and the associated interventions needed (i.e., resuscitation) contribute to acute imbalances in the hydrostatic and oncotic pressures between the intravascular and extravascular compartments, facilitating a pathologic accumulation of fluid.

Systemic inflammation, sepsis, and shock can contribute to injury and loss of integrity of the endothelium, leading to alterations in capillary permeability (i.e., capillary leak), resulting in a net loss of fluid from the intravascular compartment into the interstitial space. This is further compounded by reductions in plasma oncotic pressure (i.e., hypoalbuminemia) commonly associated with critical illness, leading to a greater driving force for fluid to leave the intravascular space as predicted by the Starling equation:

Q = Kf ([Pc – Pi] – σ[πc – πi])

In the Starling equation, Q represents the net fluid flux between the intra-vascular and extra-vascular interstitial compartments. Specifically, the term ([Pc – Pi] – σ[πc – πi]) represents the net driving force for fluid; Pc is the capillary hydrostatic pressure; Pi is the interstitial hydrostatic pressure; πc is the capillary oncotic pressure; πi is the interstitial oncotic pressure; σ is the reflection coefficient; and Kf is the proportionality constant.

In addition, crystalloid solutions most commonly used in acute resuscitation, depending on their tonicity, are readily redistributed after administration. For example, isotonic fluids (i.e., 0.9% normal saline) tend to distribute 3:1 between the intra-vascular and interstitial space; however, more hypotonic solutions will distribute across all body compartments, with only a small proportion remaining in the intra-vascular compartment.

This ratio may be further compounded by alteration in endothelial function and the development of capillary leak, hypoalbuminemia, and increased capillary hydrostatic pressure. Analogous to endothelial injury, the alveolar epithelium is also susceptible to injury from systemic inflammation, sepsis, and shock. Alveolar edema may occur via transfer of fluid from the capillary interstitial space to the alveolar airspaces due to elevated hydrostatic pressure (i.e., left atrial hypertension), increased permeability, and/or a combination of either.

In addition, organ injury and failure, in particular AKI, can further contribute to fluid accumulation. AKI in critical illness is common and often multi-factorial (i.e., sepsis, nephrotoxins, intra-abdominal hypertension), and is characterized by a rapid and sustained decline in GFR. This is clinically manifest by an increase in serum creatinine and/or a progressive reduction in urine output. This interrupts fluid and electrolyte homeostasis and markedly reduces the capacity for free water and solute excretion. Fluid and solute retention can be further compounded by increased activation of the sympathetic nervous system, the renin-angiotensin-aldosterone axis, and stimulation of non-osmotic release of AVP.

In critical illness, systemic inflammation and shock contribute to a reduced effective circulation, reduced oncotic pressure gradient (i.e., hypoalbuminemia), and alterations to capillary permeability as aforementioned, which demand a high obligatory fluid intake (i.e., active resuscitation, intravenous medications) to restore and maintain intravascular volume homeostasis. Recent data also support the notion that AKI in itself can further incite systemic inflammation and lead to distant organ dysfunction. In experimental studies, kidney ischemia/reperfusion injury (IRI) was associated with significant down-regulation of alveolar sodium channel receptors and Na-K-ATPase and aquaporin expression, implying impaired alveolar sodium and fluid homeostasis in AKI.

Similar IRI models of AKI have also shown increased pulmonary vascular permeability within 24 hours of kidney injury that correlated with changes in kidney function. These observations have important implications for how AKI (and fluid therapy in AKI) may incite or exacerbate ALI and contribute to extravascular lung water accumulation. Fluid accumulation and overload can also affect kidney function and worsen AKI, creating in essence a positive feedback loop.

For example, fluid overload may contribute to or worsen intra-abdominal hypertension, in particular in critically ill trauma or burn-injured patients, leading to further reductions in renal blood flow, venous outflow, renal perfusion pressure, and urine output. Mechanical ventilation and positive end-expiratory pressure (PEEP), by increasing intrathoracic pressure, can alter kidney function and contribute to fluid accumulation through stimulation of an array of hemodynamic, neural, and hormonal responses that act on the kidney to reduce renal perfusion, reduce GFR, and inhibit excretory function.

Epidemiology

The incidence of volume overload in hospitalized patients is largely unknown. However, the epidemiology and outcomes associated with volume overload have been characterized slightly better in selected cohorts, such as patients undergoing colorectal or cardiac surgery, or with diagnoses of congestive heart failure, acute kidney injury, acute lung injury, septic shock, or other forms of critical illness in general.

With the exception of elective surgery, these diagnoses are all generally associated with critical illness that is characterized by increased illness severity and organ dysfunction, prompting the need for fluid resuscitation and ongoing physiologic support often characterized by large obligatory fluid intake (i.e., medications, nutrition). As such, fluid accumulation in critical illness may be inevitable in the early phases of resuscitation and is likely far more common than appreciated.

Risk Identification - Fluid accumulation represents the balance between all fluids administered and all fluid losses over a given observation period. This can be further quantified as the % fluid overload (%FO) as previously defined, whereby a %FO value of >10% is a common metric used to define fluid overload.

Several factors can influence the rate and severity of fluid accumulation in critically ill patients. The administration of large volumes of fluid therapy, either as repeated boluses or as a continuous “maintenance” infusion, likely represents the majority of all fluid administered. However, there are several additional “occult” sources of fluid administration that may be less appreciated as significant contributors to overall fluid accumulation, such as fluid used to piggyback antimicrobials or other medications, small-volume continuous infusions used to maintain patency of central and/or peripheral venous access, enteric and/or parenteral nutrition, and transfused blood products.

In addition, there are clinical factors, such as an episode of oliguria that prompt the administration of a fluid challenge to improve urine output. While under-resuscitation should be avoided and administration of a fluid challenge would be an appropriate course in circumstances of intra-vascular volume depletion, this can be difficult to discriminate from oliguria due to other etiologies. As previously discussed, further fluid administration in critically ill patients with apparent optimized systemic hemodynamics and replete intravascular volume (i.e., no further improvement following a fluid challenge) will not likely improve either kidney function or oliguria, but rather will lead to worsening fluid accumulation with ensuing impairment in gas exchange and pulmonary edema. The tendency to simply administer a fluid challenge to critically ill patients with oliguric AKI may further compound fluid accumulation and contribute to complications.

In addition, there are several factors with the potential to exacerbate fluid accumulation related to pathologic fluid retention and impaired excretion. These may include, but are not limited to, pre-existing comorbid disease (i.e., chronic kidney disease, heart failure, chronic obstructive pulmonary disease), acute oliguric AKI leading to a further reduction in capacity for free water and sodium excretion, impaired myocardial performance with counter-regulatory hormone activation, intra-abdominal hypertension, and PEEP during mechanical ventilation contributing due to non-osmotic release of arginine vasopressin.

Brandstrup and colleagues randomized 172 patients undergoing elective colorectal surgery to either a restricted fluid regiment (i.e., goal-oriented replacement of measured peri-operative fluid losses) or a standard intra- and post-operative fluid regimen generally recognized to greatly exceed the observed peri-operative fluid losses by a measure of approximately 3-7 kg of weight gain in the post-operative period. The occurrence of post-operative complications was significantly reduced in those allocated to a restricted fluid regimen (33% vs. 51%, p = 0.01) when compared to the standard of care. These observations have now been similarly described in patients undergoing major intra-abdominal and cardiothoracic surgery.

Fluid accumulation and overload have also been associated with worse clinical outcomes and increased health resource use, including prolonged stay in ICU and hospital, escalation in therapy (i.e., ICU admission, repeat surgical procedures, initiation of RRT), and higher short-term mortality.

In a small retrospective study of 36 critically ill patients with septic shock, Alsous and colleagues found a higher mortality in those not achieving a negative fluid balance in at least one of the first three days following ICU admission.

Several clinical studies of critically ill children with AKI have consistently identified fluid overload, defined as a %FO >10%, as an important independent factor associated with mortality. Moreover, the severity of fluid overload has also shown a “dose-response” with worse clinical outcome. Goldstein and colleagues evaluated critically ill children with AKI and found that a higher %FO at the time of initiation of continuous RRT, after adjustment for illness severity, was independently associated with lower survival. This observation has now been confirmed in several additional investigations of critically ill children with multi-organ dysfunction syndrome and AKI. In fact, in critically ill children, achieving a %FO >10% is now recognized as an indication for initiation of RRT to restore volume homeostasis.

In a further analysis of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, Payen and colleagues examined the influence of fluid balance on survival of critically ill patients with AKI. In this study, patients were compared by whether they developed AKI, defined by a renal Sequential Organ Failure Assessment (SOFA) score ≥2 or by urine output <500 mL/day. Of the 3,147 patients enrolled, 1,120 (36%) developed AKI with 75% occurring within two days of ICU admission. Mortality at 60 days was higher for those with AKI (36% vs. 16%, p < 0.01). In patients with both early- and late-onset AKI, average daily fluid balances through the first seven ICU days were significantly more positive compared to non-AKI patients (p < 0.05 for each day).

More recently, Bouchard and colleagues performed a secondary analysis of the 610 critically ill patients with AKI enrolled in the PICARD study to evaluate the association of fluid overload, defined as a %FO >10%, and 60-day mortality. Patients with fluid overload had higher illness severity and treatment intensity, were more likely post-operative, and had lower serum creatinine and urine output at the time of enrollment. Crude mortality at 60 days was significantly higher for AKI patients with fluid overload (48% vs. 35%, p = 0.006).

The adjusted odds of death for fluid overload at the time of AKI diagnosis was 3.1 (95% CI, 1.2-8.3). In those patients receiving RRT, average fluid accumulation was significantly lower in survivors compared with non-survivors (8.8% vs. 14.2%, p = 0.01) and the adjusted odds for death for fluid overload at RRT initiation was 2.1 (95% CI, 1.3-3.4). Moreover, there was evidence of near-linear increases in mortality when stratified by cumulative fluid accumulation over the duration of hospitalization, along with higher mortality for those patients with greater duration of being classified as fluid overloaded (p < 0.0001).

The data from these pediatric and adult observational investigations provide compelling evidence that attention to fluid balance and prevention of volume overload, in particular in AKI, may be an important and under-appreciated determinant of survival.

Risk Modification – There are a few notable studies that have evaluated the impact of fluid management strategies in critically ill patients at risk for fluid accumulation on clinical outcomes.

Brandstrup and colleagues randomized 172 patients undergoing elective colorectal surgery to either a restricted fluid regimen (i.e., goal-oriented replacement of measured peri-operative fluid losses) or a standard intra- and post-operative fluid regimen generally recognized to greatly exceed the observed peri-operative fluid losses by a measure of approximately 3-7 kg of weight gain in the post-operative period. While there was no difference in mortality, the occurrence of post-operative complications was significantly reduced in those allocated to a restricted fluid regimen (33% vs. 51%, p = 0.01) when compared to the standard of care. These observations have now been similarly described in patients undergoing major intra-abdominal and cardiothoracic surgery.

In a small cohort of critically ill patients with pulmonary edema, defined as having high extravascular lung water (EVLW > 7 mL/kg) content, Shuller and colleagues found that those patients who accumulated <1 L of fluid by 36 hours after enrollment has a higher survival (74% vs. 50%, p < 0.05). In multivariable analysis adjusting for illness severity, less fluid accumulation was an independent predictor of survival. Moreover, less fluid accumulation was also associated with fewer days of mechanical ventilation, shorter ICU stay, and reduced duration of hospitalization.

This study was one of the first to show that measurement of fluid balance has clinical relevance and that adopting a fluid management strategy to achieve a neutral or negative fluid balance in selected patients, after their initial acute resuscitation, may contribute to improved clinical outcomes without compromising the hemodynamic profile of the patient or precipitating additional organ dysfunction such as AKI.

These observations have subsequently been confirmed in larger studies of critically ill patients with acute lung injury. In a secondary analysis of the SOAP study, Sakr and colleagues found that a greater mean fluid balance was independently associated with higher mortality in a cohort of septic critically ill patients with ALI or ARDS.

In a pilot trial of critically ill patients with ALI and hypoproteinemia (serum albumin < 20 g/L), Martin and colleagues evaluated the efficacy of a continuous infusion of furosemide combined with supplemental albumin administration (25 g every 8 hours) compared with placebo on fluid balance, hemodynamics, and measures of pulmonary physiology. While there was no difference in mortality, those allocated to furosemide plus albumin achieved a significantly greater net diuresis and weight loss, along with improvements in hemodynamics and gas exchange during the study.

Recently, the ARDS Clinical Trials Network reported a randomized trial comparing conservative and liberal fluid management strategies following acute resuscitation for critically ill patients with ALI. The mean (SD) cumulative fluid balance during the first 7 days was -136 (491) mL in the conservative and 6,992 (502) mL in the liberal group (p < 0.001).

While there was no statistical difference in the primary outcome of 60-day mortality (25.5% for conservative vs. 28.4% for liberal, p = 0.30), those allocated to the restrictive regimen showed improvement in lung function, received fewer days of mechanical ventilation, and had shorter duration of stay in ICU. Importantly, the conservative regimen did not increase the incidence of shock, non-pulmonary organ dysfunction, or requirement of RRT.

These clinical studies would appear to strongly support the concept of a conservative fluid strategy, after acute resuscitation has been completed, in critically ill patients.

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